1. Technical Field
The present invention relates to a method of fibrin sealant preparation and delivery, which permits use of a single delivery device. The method may be used for autologous, single-donor, pooled-donor or cell culture-derived fibrin sealant for various human and veterinary surgical procedures. The invention further relates to a kit suitable for use in such a method.
2. BACKGROUND INFORMATION
The blood coagulation system is a complex series of proteins and factors which are activated sequentially to produce a fibrin gel or clot. In the final stages of the process, fibrinogen is cleaved by thrombin to generate fibrin monomer, which rapidly polymerizes and is cross-linked by activated Factor XIII to form a fibrin matrix.
Preparations of human coagulation factors, including fibrinogen and thrombin, have been used extensively in surgery over the last ten years (Schlag et al (eds), Fibrin Sealant in Operative Medicine, vol 1-7, Springer-Verlag, Heidelberg). These biological fibrin sealants promote hemostasis and wound healing by sealing leakage from tissues, sutures, staples, and prostheses, and are particularly useful during open heart surgery in heparinized patients. The sealants also have use as an adhesive for the bonding of tissues and they reduce the amount of blood required for transfusions by controlling intraoperative bleeding. Their effectiveness is reflected in the extensive range of surgical applications for which they have been used, including cardiovascular surgery, plastic surgery, orthopedics, urology, obstetrics and gynecology, dentistry, maxillofacial and ophthalmic surgery.
Fibrin sealant products prepared from pooled human plasma fibrinogen/Factor XIII are available commercially in Europe (Tissucol/Tisseel, Immuno AG, Vienna, Austria and Beriplast P, Hoechst, West Germany) but such products have not received U.S. Food and Drug Administration approval. As an alternative, some hospitals are preparing fibrin sealant in-house using the patient's own blood (autologous) or single-donor (homologous) plasma as a source of fibrinogen and Factor XIII.
The plasma fibrinogen/Factor XIII component of fibrin sealant is typically prepared by freezing plasma at a temperature below -20.degree. C. overnight, slowly thawing the material at 0.degree.-4.degree. C., centrifuging, and transferring the cryoprecipitate to a syringe or spray container (Dresdale et al, Ann. Thorac. Surg. 40:385 1985; and U.S. Pat. No. 4,627,879). The thrombin component, usually purified from bovine plasma, can be obtained commercially and is typically prepared in a separate syringe or spray container. In use, the two solutions are delivered simultaneously or alternately to generate fibrin sealant at the site of the wound; alternatively, the sealant is applied to a collagen matrix (e.g. Gelfoam or Avitene) and then pressed against the site (Lupinetti et al, J. Thorac. Cardiovasc. Surg. 90:502 1985; and U.S. Pat. No. 4,453,939).
The use of fibrin sealant in surgery has been limited by problems associated with mixing and delivery of the sealant to the wound. Generation of fibrin sealant at the wound site is currently achieved using a two syringe or spray container system to prevent premature mixing and clotting of the components. Such two syringe systems are, however, unsatisfactory due to the awkwardness of filling and manipulating the delivery devices at the wound site. In addition, the syringe system is accompanied by problems of inadequate mixing of the two solutions, resulting in the formation of a weak clot. Alternatively, the two syringes can be placed into a holder designed such that the solutions are permitted to mix before entering the needle (U.S. Pat. Nos. 4,735,616, 4,359,049, and 4,631,055). The mixing chamber directs the flow of the separate components through two narrow channels and forces mixing at the top of the outflow needle. Although the strength of the clot obtained using this method is reproducible, the needle frequently clogs and must repeatedly be replaced.
In view of the problems inherent in the methodologies currently available for delivering fibrin sealant, the need for a simple, reproducible technique is clear. Such a technique must be convenient to use and must result in the formation, at a specific site, of a clot of appropriate strength. Such a delivery technique is provided by the invention disclosed herein.